Association of Kidney Comorbidities and Acute Kidney Failure With Unfavorable Outcomes After COVID-19 in Individuals With the Sickle Cell Trait
Authors: Anurag Verma, Jennifer E. Huffman, Lina Gao, Jessica Minnier, Wen-Chih Wu, Kelly Cho, Yuk-Lam Ho, Bryan R. Gorman, Saiju Pyarajan, Nallakkandi Rajeevan, Helene Garcon, Jacob Joseph, John E. McGeary, Ayako Suzuki, Peter D. Reaven, Emily S. Wan, Julie A. Lynch, Jeffrey M. Petersen, James B. Meigs, Matthew S. Freiberg, Elise Gatsby, Kristine E. Lynch, Seyedeh Maryam Zekavat, Pradeep Natarajan, Sharvari Dalal, Darshana N. Jhala, Mehrdad Arjomandi, Robert A. Bonomo, Trevor K. Thompson, Gita A. Pathak, Jin J. Zhou, Curtis J. Donskey, Ravi K. Madduri, Quinn S. Wells, Joel Gelernter, Rose D. L. Huang, Renato Polimanti, Kyong-Mi Chang, Katherine P. Liao, Philip S. Tsao, Yan V. Sun, Peter W. F. Wilson, Christopher J. O’Donnell, Adriana M. Hung, J. Michael Gaziano, Richard L. Hauger, Sudha K. Iyengar, Shiuh-Wen Luoh, Sumitra Muralidhar, Jean Beckham, Jennifer Moser, Lauren Thomann, Helene Garcon, Nicole Kosik, Scott D. Damrauer, Themistocles Assimes, Panagiotis Roussos, Robert Striker, Sony Tuteja, Scott L. DuVall, Kristine E. Lynch, Elise Gatsby, Rachel Ramoni, James Breeling, Grant Huang, Stacey B. Whitbourne, Jessica V. Brewer, Mihaela Aslan, Todd Connor, Dean P. Argyres, Brady Stephens, Mary T. Brophy, Donald E. Humphries, Luis E. Selva, Nhan Do, Shahpoor (Alex) Shayan, Lori Churby, Elizabeth Hauser, Hongyu Zhao, Peter Wilson, Rachel McArdle, Louis Dellitalia, Kristin Mattocks, John Harley, Jeffrey Whittle, Frank Jacono, John Wells, Salvador Gutierrez, Gretchen Gibson, Kimberly Hammer, Laurence Kaminsky, Gerardo Villareal, Scott Kinlay, Junzhe Xu, Mark Hamner, Roy Mathew, Sujata Bhushan, Pran Iruvanti, Michael Godschalk, Zuhair Ballas, Douglas Ivins, Stephen Mastorides, Jonathan Moorman, Saib Gappy, Jon Klein, Nora Ratcliffe, Hermes Florez, Olaoluwa Okusaga, Maureen Murdoch, Peruvemba Sriram, Shing S Yeh, Neeraj Tandon, Darshana Jhala, Samuel Aguayo, David Cohen, Satish Sharma, Suthat Liangpunsakul, Kris A Oursler, Mary Whooley, Sunil Ahuja, Joseph Constans, Paul Meyer, Jennifer Greco, Michael Rauchman, Richard Servatius, Melinda Gaddy, Agnes Wallbom, Timothy Morgan, Todd Stapley, Scott Sherman, George Ross, Philip Tsao, Patrick Strollo, Edward Boyko, Laurence Meyer, Samir Gupta, Mostaqul Huq, Joseph Fayad, Adriana Hung, Jack Lichy, Robin Hurley, Brooks Robey
Journal: JAMA Internal Medicine (2022)

<h3>Importance</h3> Sickle cell trait (SCT), defined as the presence of 1 hemoglobin beta sickle allele (rs334-T) and 1 normal beta allele, is prevalent in millions of people in the US, particularly in individuals of African and Hispanic ancestry. However, the association of SCT with COVID-19 is unclear. <h3>Objective</h3> To assess the association of SCT with the prepandemic health conditions in participants of the Million Veteran Program (MVP) and to assess the severity and sequelae of COVID-19. <h3>Design, Setting, and Participants</h3> COVID-19 clinical data include 2729 persons with SCT, of whom 353 had COVID-19, and 129 848 SCT-negative individuals, of whom 13 488 had COVID-19. Associations between SCT and COVID-19 outcomes were examined using firth regression. Analyses were performed by ancestry and adjusted for sex, age, age squared, and ancestral principal components to account for population stratification. Data for the study were collected between March 2020 and February 2021. <h3>Exposures</h3> The hemoglobin beta S (HbS) allele (rs334-T). <h3>Main Outcomes and Measures</h3> This study evaluated 4 COVID-19 outcomes derived from the World Health Organization severity scale and phenotypes derived from<i>International Classification of Diseases</i>codes in the electronic health records. <h3>Results</h3> Of the 132 577 MVP participants with COVID-19 data, mean (SD) age at the index date was 64.8 (13.1) years. Sickle cell trait was present in 7.8% of individuals of African ancestry and associated with a history of chronic kidney disease, diabetic kidney disease, hypertensive kidney disease, pulmonary embolism, and cerebrovascular disease. Among the 4 clinical outcomes of COVID-19, SCT was associated with an increased COVID-19 mortality in individuals of African ancestry (n = 3749; odds ratio, 1.77; 95% CI, 1.13 to 2.77;<i>P</i> = .01). In the 60 days following COVID-19, SCT was associated with an increased incidence of acute kidney failure. A counterfactual mediation framework estimated that on average, 20.7% (95% CI, −3.8% to 56.0%) of the total effect of SCT on COVID-19 fatalities was due to acute kidney failure. <h3>Conclusions and Relevance</h3> In this genetic association study, SCT was associated with preexisting kidney comorbidities, increased COVID-19 mortality, and kidney morbidity.